Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species

Abstract

Aging is a global decline of physiological functions, leading to an increased susceptibility to diseases and ultimately death. Maximum lifespans differ up to 200-fold between mammalian species. Although considerable progress has been achieved in identifying conserved pathways that regulate individual lifespan within model organisms, whether the same pathways are responsible for the interspecies differences in longevity remains to be determined. Recent cross-species studies have begun to identify pathways responsible for interspecies differences in lifespan. Here, we review the evidence supporting the role of anticancer mechanisms, DNA repair machinery, insulin/insulin-like growth factor 1 signaling, and proteostasis in defining species lifespans. Understanding the mechanisms responsible for the dramatic differences in lifespan between species will have a transformative effect on developing interventions to improve human health and longevity.

Keywords: aging; comparative biology; longevity; mammals.

Fig. 1. Perturbation of insulin/IGF-1 signaling pathway in long-lived strains or species

In mammals, IGF-1 is produced primarily in the liver in response to growth hormone secreted by the pituitary gland. IGF-1 mainly functions as an endocrine hormone by activating the IGF-1 receptor (IGF1R) in distant tissues. Insulin secreted by pancreas activates the insulin receptor (INSR). IGF1R and INSR activate similar downstream signaling pathways via insulin receptor substrate (IRS) proteins, which eventually inactivate FOXO transcription factors. Multiple mechanisms that perturb the insulin/IGF-1 signaling pathway have been identified in long-lived strains or species. For example, unique mutations in the growth hormone (GH) receptor and IGF1R are identified in Brandt’s bats, which downregulate insulin/IGF-1 signaling. Long-lived mouse strains and small dogs have reduced plasma IGF-1 levels compared to their counterparts. In addition, IGF1R expression levels in the brain negatively correlate with species maximum lifespan.

Fig. 2. Molecular mechanisms determining lifespan in mammalian species

Multiple molecular mechanisms contributing to longer lifespans have been identified in long-lived mammalian species. Telomerase inhibition in large long-lived species (larger than 5–10 kg), TP53 expansion in elephants, concerted cell death (CCD) in blind mole rats, and high-molecular-mass hyaluronan (HMM-HA) in naked mole rats contribute to extraordinary cancer resistance. Strategies to enhance DNA repair capacity include upregulating the expression and altering the sequences of DNA repair genes in different species. Perturbed insulin/IGF-1 signaling due to reduced plasma IGF-1 and brain IGF1R expression or unique mutations in growth hormone receptor (GHR) and IGF1R were identified in some long-lived species. Long-lived species may protect telomeres by augmenting antioxidant response systems and upregulating shelterin proteins. Proteostasis in naked mole rats is enhanced by increasing translational fidelity, upregulating the expression of chaperones, and elevating autophagy and proteasome activity. Other longevity mechanisms identified in model organisms may contribute to longer lifespans of naturally long-lived species, which include more active sirtuins, reduced cellular senescence, repressed mTOR signaling, activated AMPK signaling and suppressed neuropeptide signaling.

Fig. 3. Evolution of longevity

Mechanisms that determine lifespan in long-lived species are composed of species-specific and conserved mechanisms. Each long-lived species has evolved unique mechanisms of longevity, in addition the conserved pathways that control aging may be differentially regulated in long-lived species relative to the short-lived ones.